The most urgent therapeutic goal for symptomatic Huntington's disease (HD) is to develop disease-modifying (neuroprotective) treatments able to slow progression. Advancing basic and translational research has identified numerous molecular targets for neuroprotection and treatments based on them are creating an expanding pipeline. However, clinical trials testing these treatments are not keeping up with the compounds for which there are compelling rationales. The development and use of biomarkers in clinical trials for HD have profound potential to increase the rate and accuracy with which compounds, and by implication their targets, can be assessed. Since HD is fundamentally a progressive neurodegenerative disease, neuro-imaging measures hold great promise as direct measures of disease progression that may also provide the necessary sensitivity and specificity to help assess disease modification in Phase II and Phase III clinical trials. During the current funding period, we have used state-of-the-art neuro-imaging tools to show that regional brain atrophy in HD is early and progressive, and correspond to clinical features, including the TFC. We also used these tools as a pharmacodynamic biomarker in a pilot study of high-dose Creatine, a leading candidate neuroprotective agent, in HD subjects. We found that high dose Creatine slowed brain atrophy, reduced measures of oxidative stress, and may have slowed cognitive decline. Through an innovative and highly novel recruitment strategy and approach, we completed the first Phase II study in individuals at risk for HD (PRECREST). We are seeking to validate our neuro-imaging tools in our NIH sponsored placebo-controlled, double-blind Phase III clinical trial of high-dose creatine as a biomarker of disease progression. Should Creatine slow progression and slow brain atrophy, it will be a crucial step in demonstrating the value of neuro-imaging as a marker of disease modification. Even in the absence of therapeutic efficacy, continuation of this project will provide invaluable information regarding the correspondence between structural and diffusion MRI measures and the clinical, temporal and biological progression of early HD.